The NF-kappaB/Rel transcription factors are present in the cytosol in an inactive state, complexed with the inhibitory IkappaB proteins. Most agents that activate NF-kappaB do so through a common pathway based on phosphorylation-induced, proteasome-mediated degradation of IkappaB. The key regulatory step in this pathway involves activation of a high molecular weight IkappaB kinase (IKK) complex whose catalysis is generally carried out by three tightly associated IKK subunits. IKKalpha and IKKbeta serve as the catalytic subunits of the kinase and IKKgamma serves as the regulatory subunit. Activation of IKK depends upon phosphorylation at Ser177 and Ser181 in the activation loop of IKKbeta (Ser176 and Ser180 in IKKalpha), which causes conformational changes, resulting in kinase activation. Activation of the NF-kappaB pathway by the T-cell lymphotrophic virus Tax protein or by TNF-alpha treatment leads to IKKbeta-dependent phosphorylation of human IKKgamma, primarily at Ser376. In mice, mutation of the orthologous residue (Ser369) to alanine leads to enhanced IKKgamma-mediated stimlulation of IKKbeta kinase activity.
